a) Field of the Invention
The present invention relates to protected aminothiazolyl acetic acid derivatives and salts thereof, which are preparation intermediates useful for introducing a 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetyl group or a 2-(2-aminothiazol-4-yl)-2-alkenoyl group into a cephem skeleton, and also to a process for the preparation thereof. The above alkoxyiminoacetyl group or alkenoyl group is a moiety common to antibiotics such as Cefmenoxime, Cefpodoxime proxetil, Cefepime, Cefpirome, Cefzopran, Cefclidine, DQ-2556 (CAS Registry No. 102253-70-3), FK-037 (CAS Registry No. 122841-12-7), E1077 (CAS Registry No.116853-25-9), and S-1108 (CAS Registry No. 105889-45-0), and the like.
b) Description of the Related Art
Antibiotics such as Cefmenoxime, Cefpodoxime proxetil, Cefepime, Cefpirome, Cefzopran, Cefclidine, DQ-2556, FK-037 and E1077 and the like contain a 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetyl group or a 2-(2-aminothiazol-4-yl)-2-alkenoyl group as a common moiety in their molecules. To obtain still higher antibacterial activities, this substituent is essential.
c) Prior Art
Upon introducing a 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetyl group or a 2-(2-aminothiazol-4-yl)-2-alkenoyl group into the cephem skeleton for the preparation of an acid amide, it has heretofore been the practice to use an active derivative, such as an acid chloride, mixed acid anhydride or active ester and the like of a 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetic acid or a 2-(2-aminothiazol-4-yl)-2-alkenoic acid, especially a 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetyl chloride or a 2-(2-aminothiazol-4-yl)-2-alkenoic acid chloride. Refer to Japanese Patent Application Laid-oepn Nos.123,189/87, 264,471/88, 264,470/88, 156,984/89, and the like.
A conventional preparation process is shown by the following reaction sheme: ##STR2## wherein A represents a nitrogen atom or a methine group, R represents a lower alkoxy group, a halogenated lower alkoxy group, a triphenylmethoxy group, a lower alkyl group or an acyloxy group, and R' and R" individually represent a hydrogen atom or a substituent group.
Conventional active derivatives including 2-(2-aminothiazol-4-yl)-2-alkoxyiminoacetyl chloride have nucleophilic reactivity, because the amino group on the thiazole ring is not protected. Therefore, the active derivative is prepared or when the amino group is reacted with the cephem skeleton to form an acid amide, a side reaction takes place on the amino group, resulting in that a high-purity active derivative or acid amide could not be obtained in a good yield. Antibiotics, as pharmaceuticals, are required to have particularly high quality. In many cases, it is therefore necessary to conduct plural purification steps. The use of these active derivatives therefore has not been considered as an industrially suited preparation process.
To control the above-described side reaction on the amino group, it is preferred to protect the amino acid in advance. A number of protecting groups are known for the amino group. No protecting group is however known to have stability in various reactions and readily removable property under mild conditions, as well as economical merits. Upon conducting a target investigation with a view toward inter alia improving the purity of a product, reducing its production cost and improving the process operability, it was found that such conventional amino-protecting groups are improper. In order to achieve the target, there has been desidered the development of a novel protected aminothiazolylacetic acid derivative.